Diabetic cardiomyopathy, a disease of the heart muscle (myocardium), is considered a distinct medical entity from either diabetes or cardiovascular disease. Diabetic cardiomyopathy occurs in patients having insulin dependent diabetes mellitus (Type 1) and in patients having non-insulin dependent diabetes mellitus (Type 2). Diabetic cardiomyopathy clinically expresses itself as congestive heart failure (CHF) and left ventricular hypertrophy. Diabetic cardiomyopathy is also associated with increased morbidity and mortality. Pathologically, diabetic cardiomyopathy is characterized by myocellular hypertrophy, interstitial fibrosis, increased myocardial lipid deposition, and varying degrees of small vessel disease. Diabetic cardiomyopathy differs from ischemic cardiomyopathy because the diseased myocardium and resultant CHF can occur in the absence of frank coronary atherosclerosis or luminal narrowing. This suggests that the primary metabolic defects related to hyperglycemia that exist in the myocardial tissue and/or in the coronary microcirculation itself are responsible for the diseased state and loss of myocardial function in diabetics. Co-existent hypertension, microvascular complications, impaired fibrinolysis, atherosclerotic cardiovascular disease, and/or myocardial ischemia, which frequently occur in diabetic patients, compound the severity of the underlying diabetic cardiomyopathy. These co-morbidities can lower the threshold for decompensated heart failure, pulmonary edema, and arrhythmias, which can result in the death of the patient.
Diabetic cardiomyopathy can in part explain the increased mortality and morbidity seen in diabetic patients following myocardial infarction or certain cardiovascular interventions, such as coronary artery bypass graft surgery or angioplasty. The microvascular diseases associated with diabetes, e.g. thickened arterial intima (arteriolar hyalinization), microaneurisyms of myocardial arterioles, increased capillary basement membrane thickening, and abnormalities in endothelial metabolism, as well as an impaired fibrinolysis, can contribute to compromised regional blood flow in the heart, resulting in “non-obstructive” ischemia and injury.
Diabetic cardiomyopathy is associated with mechanical dysfunction of the heart. The hypertrophied fibrotic myocardium has reduced compliance, leading to diastolic dysfunction and an elevated left ventricular filling pressure. Progression of the cardiomyopathic process may ultimately result in impairments in myocardial contraction and systolic dysfunction. A reduced stroke volume, low ejection fraction, and impaired cardiac reserve will cause a further rise in left ventricular filling pressures. This may result in fulminant heart failure. This pathophysiology can be reproduced and studied in animal models of diabetic cardiomyopathy.
The underlying cause of diabetic cardiomyopathy appears to be related to hyperglycemia and insulin resistance. The condition is exacerbated by co-existing hypertension. Hyperglycemia causes “glucose toxicity,” the exact nature of which is unknown, but may include abnormal myocardial carbohydrate, lipid, and adenine nucleotide metabolism, altered tissue oxygen demand, excess protein and tissue glycosylation, formation of damaging advanced glycation end-products, stimulation of smooth muscle proliferation, increased adhesiveness and aggregation of platelets, and increased production of PAI-1, among other things. These hyperglycemia-associated perturbations contribute to myocardial biochemical changes (e.g. defective cellular metabolism, calcium transport, excess collagen formation) that are observed in the diseased state of the myocardium in diabetics.
The major cause of morbidity and mortality in the diabetic population is cardiovascular disease (CVD). Coronary heart disease (CHD), also referred to as coronary artery disease (CAD), the major cause of myocardial infarction and stroke, and peripheral vascular disease (PVD) are all manifestations of CVD. It is well recognized that diabetics have increased risk of mortality from CVD, which has been primarily attributed to the hyperglycemia associated with their disease, independent of other associated co-morbidities, such as obesity, hypertension, atherosclerosis, and dyslipidemia. The independent risk due to hyperglycemia is often difficult to distinguish in some diabetics, because they also usually possess several of the other co-morbidities mentioned above. Further, their hyperglycemia can exacerbate the severity of the other co-morbidities, leading to interactive effects. Nonetheless, several studies have identified hyperglycemia as a strong independent risk factor even in diabetics with other significant risk factors present. Hyperglycemia is a prime candidate for causing this excess risk, and contributing to the high morbidity and mortality due to CVD in people with diabetes because hyperglycemia causes glucose toxicity. Agents that can reduce glucose toxicity may have beneficial effects on the manifestations of chronic cardiomyopathy, but also may provide more immediate cardioprotection.
Pharmacological cardioprotection can be defined as the use of an agent to protect the myocardium from ischemic or reperfusion injury. The pharmacological agent may, for example, protect heart cells from damage, necrosis, or apoptosis during ischemic or reperfusion injury by mimicking ischemic preconditioning, which is a naturally occurring, physiologic phenomenon that provides endogenous cardioprotection. The cardioprotective effects, depending on the agent used, may be both immediate (minutes-hours) or delayed (24-72 hours) post-ischemia. Cardioprotective agents may be useful for reducing both perioperative and non-perioperative ischemic injury. Cardioprotective agents may be especially useful in diabetics who are at increased risk of both acute myocardial infarction and chronic cardiomyopathies.
U.S. Pat. No. 5,990,111 discloses the treatment of diabetic cardiomyopathy using an aldose reductase inhibitor.